Oral tolerance to foods normally develops during the first few years of life. An aberration of oral tolerance, food allergy, occurs in 6% of children and 3.5% of adults in the United States. Peanut allergy is one of the most common of the food allergies occurring in 1% of young children. Interestingly, approximately only 20% of young children with peanut allergy will develop oral tolerance to peanuts by age five. We propose to utilize a form of treatment, sublingual immunotherapy (SLIT) to investigate and possibly hasten the development of oral tolerance to peanuts. This application is based on data from our work and others that allergen-specific SLIT will desensitize and possibly tolerize peanut-allergic subjects. There have not been well-designed previous studies of SLIT for food allergy that have been scientifically rigorous. Our hypothesis is that instituting peanut allergen SLIT early after development of food allergy will clinically desensitize patients by altering basophil/mast cell reactivity and will cause clinical tolerance to develop because of the activity of allergen- specific T regulatory cells. This proposal is based on our preliminary studies that have examined the effects of SLIT in older children with peanut allergy and of oral immunotherapy in peanut- and egg-allergic children. Our approach will be to enroll two cohorts of subjects who have peanut sensitivity (peanut specific IgE > 7 KU/L and significant initial symptoms); one group soon after their development (ages 1 to 5 years) and the second group who have not outgrown their peanut allergy (ages 6 to 11 years) and treat them with peanut SLIT in a prospective randomized, blinded SLIT protocol. We will study the basophil/mast cell reactivity, antigen-specific T cell responses and mucosal and systemic humoral immune responses in these subjects. We are combining the expertise of scientific investigators from the fields of allergy, immunology and pathology and the resources of our NIH-funded GCRC for our studies. Our specific aims are: (1) Determine if allergen-specific SLIT will cause clinical desensitization and tolerance to develop in peanut allergic young children, (2) Determine if the development of the desensitized state to peanut is associated with the down-regulation of mast cells and basophils, (3) Determine if the development of clinical tolerance to peanuts is associated with an increase in the T regulatory phenotype of antigen-activated peripheral CD4+ T cells and (4) Determine the effect of peanut-specific mucosal and systemic humoral immune responses in SLIT on desensitization and oral tolerance. Completion of the studies will provide new information regarding the cellular and molecular mechanisms of action of oral tolerance and allergen-specific SLIT and provide the foundation for the development of novel treatments for food allergy. PUBLIC HEALTH RELEVANCE - PROJECT NARRATIVE: The project is designed to develop a treatment for food allergy. Food allergy effect 6% - 8% of young children and 4% of adults and there are no current preventive treatment available. The development of a treatment and understanding the mechanism of how it works is important for the future treatment of patients with food allergy.